Retinal degeneration is one of the leading causes of visual loss in the world. Autoimmune retinopathies, including paraneoplastic retinopathies such as cancer-associated retinopathy and melanoma-associated retinopathy, are progressive visual impairments that are mediated by autoantibodies against retinal proteins. Autoimmune retinopathy is currently an untreatable eye disease, and an understanding of its pathogenicity is still incomplete. [unreadable] [unreadable] The proposed hypothesis is that autoantibodies induce retinopathy through the activation of apoptotic death in retinal cells by increasing intracellular calcium. A massive death of retinal cells leads to significant tissue damage, loss of vision, and finally, blindness. To determine general treatment strategies, assessment is needed of a common mechanism of retinopathy that is associated with autoantibodies of various retinal specificities. [unreadable] [unreadable] The long-term goal is to define the mechanism of retinal damage in autoimmune retinopathy and, based on these findings, to identify precise, critical time points for therapeutic intervention to treat clinical symptoms. The objectives of this proposal are to establish pathogenic properties of patients' anti-retinal antibodies using an in vivo rat model and in vitro methods, and to define clinical and electrophysiological markers (indicators) for seropositive patients in order to initiate optimum medical evaluation and care for these patients. To achieve these objectives, the following specific aims are proposed: (1) To determine whether autoantibodies of different anti-retinal specificities activate the same mechanism in initiating apoptosis in vitro, (2) To define the phenotype of retinopathy patients with specific anti-retinal autoantibodies, (3) To determine the role of autoantibodies in altering the function of retinal cells using the rat model and electroretinography, and (4) To examine possible pathways to stop apoptosis in treating retinal degeneration in the rat model of antibody-induced retinopathy. [unreadable] [unreadable]